Process for preparing a lactone

ABSTRACT

A new synthesis of key prostaglandin precursors and intermediates employed in their preparation. The novel synthetic sequence of this invention is shorter and more efficient than those previously employed to prepare to key intermediate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 720,239 filedSept. 3, 1976 and now abandoned which, in turn, is a division ofapplication Ser. No. 633,222 filed Nov. 19, 1975 and now U.S. Pat. No.3,992,438 which, in turn, is a division of application Ser. No. 409,068filed Oct. 24, 1973 and now U.S. Pat. No. 3,943,151.

BACKGROUND OF THE INVENTION

This invention relates to a novel synthesis of certain key prostaglandinprecursors. In particular, it relates to the synthesis of lactone esteralcohol (8). Several routes already exist for the preparation of thisalcohol first described by E. J. Corey in the Journal of AmericanChemical Society Vol. 93, p 1491 (1971). However all of the existingmethods for the preparation of this important intermediate involve manysteps which frequently give rise to reduced yields. The sequences of thepresent invention are short and proceed in high yield and require aninexpensive and readily available starting material.

The prostaglandins are C-20 unsaturated fatty acids which exhibitdiverse physiological effects. For instance, the prostaglandins of the Eand A series are potent vasodilators (Bergstrom, et al., Acta Physiol.Scand. 64:332-33 1965 and Bergstrom, et al., Life Sci. 6:449-455, 1967)and lower systemic arterial blood pressure (vasodepression) onintravenous administration (Weeks and King, Federation Proc. 23:327,1964; Bergstrom, et al., 1965, op. cit.; Carlson, et al., Acta Med.Scand. 183:423-430, 1968; and Carlson, et al., Acta Physiol. Scand.75:161-169, 1969). Another well known physiological action for PGE₁ andPGE₂ is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969).

Still another important physiological role for the naturalprostaglandins is in connection with the reproductive cycle. PGE₂ isknown to possess the ability to induce labor (Karim, et al., J. Obstet.Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion(Bygdeman, et al., Contraception, 4, 293 (1971) and to be useful forcontrol of fertility (Karim, Contraception, 3, 173 (1971)). Patents havebeen obtained for several prostaglandins of the E and F series asinducers of labor in mammals (Belgian Patent No. 754,158 and West GermanPatent No. 2,034,641), and on PGF₁, F₂, and F₃ for control of thereproductive cycle (South African Patent 69/6089). It has been shownthat luteolysis can take place as a result of administration of PGF₂α[Labhsetwar, Nature 230 528 (1971)] and hence prostaglandins haveutility for fertility control by a process in which smooth musclestimulation is not necessary.

Still other known physiological activities for PGE₁ are in theinhibition of gastric acid secretion (Shaw and Ramwell, In: WorcesterSymp. on Prostaglandins, New York, Wiley, 1968, p. 55 -64) and also onplatelet aggregation (Emmons, et al., Brit. Med. J. 2:468-472, 1967).

It is now known that such physiological effects will be produced in vivofor only a short period, following the administration of aprostaglandin. A substantial body of evidence indicates that the reasonfor this rapid cessation of activity is that the natural prostaglandinsare quickly and efficiently metabolically deactivated by β-oxidation ofthe carboxylic acid side-chain and by oxidation of the 15α-hydroxylgroup (Anggard, et al., Acta. Physiol. Scand. 81, 396 (1971) andreferences cited therein). It has been shown that placing a 15-alkylgroup in the prostaglandins has the effect of increasing the duration ofaction possibly by preventing the oxidation of the C15-hydroxyl [Yankeeand Bundy, JACS 94, 3651 (1972)], Kirton and Forbes, Prostaglandins, 1,319 (1972).

It was, of course, considered desirable to devise new syntheticsequences which would be shorter and more efficient than the previouslyexisting methods. In particular, sequences which required simplestarting materials and did not require complex isolation procedures orlong and tedious purifications for the various intermediates as do theexisting prostaglandin synthesis were sought.

SUMMARY OF THE INVENTION

The present invention comprises a process for the preparation of acompound of the structure: ##STR1## wherein X is a halogen, whichcomprises contacting a halo lactone acid of the structure: ##STR2## withabout an equimolar amount of a lower alkyl chlorocarbonate and atrialkyl amine in a reaction-inert solvent at a temperature of fromabout -20° to 10° C. until reaction is substantially complete andreduction of the mixed anhydride so formed with about one to twoequivalents of sodium or zinc borohydride at a temperature of from about-20° to 20° C. until reaction is substantially complete and isolation ofproduct. The invention further embraces the process wherein the abovestarting halo lactone acid (5) is prepared by a process comprisingcontacting a halo keto acid of the structure: ##STR3## with about anequimolar amount of peracetic acid in a reaction inert solvent at atemperature of from about 25°-40° until reaction is substantiallycomplete and isolating the product so produced. Similarly, embraced isthe process wherein the above starting halo keto acid (4) is prepared bya process comprising contacting a tricyclene keto acid of the structure:##STR4## with 100-200 times its weight of concentrated hydrochloric acidat a temperature of from about 100°-150° C. until reaction issubstantial complete and isolating the product so produced. Thisinvention also includes a process wherein the above starting tricycleneketo acid (3) is prepared by a process comprising contacting a diesterof structure: ##STR5## with about an equimolar amount of CrO₃ in areaction inert solvent at a temperature of from about 0°-30° C. untilreaction is substantially complete and isolating the product soproduced. The instant invention further comprises a process wherein theabove starting diester is prepared by a process comprising contacting acompound of structure: ##STR6## with about an equimolar amount offormaldehyde and with 5-10 times its weight of formic acid in presenceof sulphuric acid at a temperature of from about 0°-30° C. untilreaction is substantially complete and isolating the product soproduced.

Also included in the invention is a process for the preparation of adilactone of the structure: ##STR7## which comprises contacting a ketolactone of the structure: ##STR8## with about an equimolar amount ofperacetic acid or a perbenzoic acid in a reaction-inert solvent at atemperature of from about 0°-40° C. until reaction is substantiallycomplete and isolation of product. Likewise included in the instantinvention is a process wherein the above starting keto lactone (15) isprepared by a process comprising contacting tricyclene keto acid (3)with about fifty times its weight of dilute sulphuric acid at atemperature of from about 100°-175° C. until reaction is substantialcomplete and isolating the produce so produced. This invention alsocomprises a process wherein the keto lactone (15) is prepared by aprocess comprising contacting a ketal lactone of structure: ##STR9##with aqueous mineral acid until reaction is substantially complete andisolating the produce so produced. This invention further comprises aprocess wherein the above starting ketal lactone (14) is prepared by aprocess comprising contacting a ketal ether of structure: ##STR10## withabout two times its weight of rutherium tetraoxide in presence of anaqueous alkali metal periodate in a reaction inert solvent untilreaction is substantially complete and isolating the product so producedand the process wherein the starting ketal ether (13) is prepared by aprocess comprising contacting an alcohol ketal of structure: ##STR11##with about equimolar amount of mercuric acetate in aqueoustetrahydrofuran until reaction is substantially complete and contactingthe organomercurial so formed with a solution of about one equivalent ofsodium borohydride in alkali metal hydroxide until reaction issubstantially complete and isolating the product so produced. Theinstant invention further comprises a process wherein the startingalcohol ketal is prepared by a process comprising contacting a ketoalcohol of structure: ##STR12## with ethylene glycol and a catalyticamount of a strong acid in refluxing reaction inert solvent withazeotropic removal of water produced until reaction is substantiallycomplete and isolating the product so produced and the process whereinthe starting keto alcohol (11) is prepared by a process comprisingcontacting the known compound of structure: ##STR13## with about onetenth its weight of Boron trifluoride in acetic anhydride at atemperature of from about 0°-20° until reaction is substantiallycomplete and contacting the acetoxy ketone so formed with about oneequivalent of aqueous base until reaction is substantially complete andisolation of product.

This invention also comprises novel compounds of the structure:##STR14## wherein X is oxygen or ##STR15## a compound of the structure:##STR16## wherein X is chlorine, bromine or iodine; a compound of thestructure: ##STR17## wherein X is chlorine, bromine or iodine; acompound of the structure: ##STR18## wherein X is chlorine, bromine oriodine; a compound of the structure: ##STR19## a compound of thestructure: ##STR20## wherein R is hydrogen or lower alkyl, a compound ofthe structure: ##STR21## wherein X is oxygen or ##STR22## a compound ofthe structure: ##STR23## wherein X is oxygen or ##STR24## , and acompound of the structure: ##STR25##

Furthermore, the instant invention also comprises a process wherein thehalo lactone 6 is prepared by a process comprising contacting a haloketone of structure: ##STR26## with one equivalent of peracetic acid ina reaction inert solvent at a temperature of from about 20°-40° C untilreaction is substantially complete and isolating the product so formedand a process wherein the starting halo ketone (27) is prepared by aprocess comprising contacting a ketone of structure: ##STR27## wherein Ris lower alkyl; with 10-100 times its weight of concentratedhydrochloric acid at a temperature of from about 100°-150° untilreaction is substantially complete and isolating the product so formed.

In addition the instant invention comprises a process wherein thetricyclene ketone (26) is prepared by a process comprising contacting atricyclene alcohol of structure: ##STR28## wherein R is lower alkyl;with about two equivalents of CrO₃ in a reaction inert solvent at atemperature of from about 0°-25° until reaction is substantiallycomplete and isolating the product so formed and

a process wherein the starting tricyclene alcohol (25) is prepared by aprocess comprising contacting a diol of structure: ##STR29## with oneequivalent of lower alkanoic acid anhydride and a proton acceptor in areaction inert solvent at a temperature of from about 0°-50° C untilreaction is substantially complete and isolating the product is formed.

Also included in the present invention is a process wherein the diol(24) is prepared by a process comprising contacting a compound of thestructure: ##STR30## wherein R is hydrogen or lower alkyl; with anaqueous solution of an alkali metal hydroxide or carbonate at atemperature of from about 0°-25° C until reaction is substantiallycomplete,

a process for the preparation of a lactone of the structure: ##STR31##which comprises contacting the halo lactone alcohol (6) with anequimolar amount of dihydropyran in presence of a catalytic amount of astrong acid and contacting the resulting ether with an equimolar amountof alkali metal hydroxide and twenty times its weight of 30% hydrogenperoxide in aqueous THF at a temperature of from about -10° to 30° Cuntil reaction is substantially complete and isolation of product and

a process wherein the lactone (7) so produced is then treated with aboutan equimolar amount of p-biphenyl carbonyl chloride in ten times itsweight of pyridine until reaction is substantially complete and thentreatment with an excess of dilute mineral acid for removal of THP groupto produce a compound of the structure: ##STR32## and the productisolated.

DETAILED DESCRIPTION OF THE INVENTION

The starting material for the novel synthesis sequences of thisinvention is norbornadene. This substance is contacted (1→2) withformaldehyde or paraformaldehyde in the presence of formic acid with asmall amount of mineral acid as a catalyst. If it is desired to producea diester other than diformate (2) acetic acid or other lower alkanoicacid may be substituted for the formic acid in this reaction. Thereaction is conveniently conducted between 0°-30° although hightemperatures may be employed if decomposition of the final product isnot encountered. Diformate (2) is then oxidized (2→3) using Jones'reagent at a reaction temperature of from about 0°-30°. The reaction isconducted in acetone as a solvent optimally at 25°. Keto acid (3) isconverted to keto acid (4) wherein X is chlorine by heating (3) inconcentrated hydrochloric acid at a temperature of from about 100°-150°.Approximately 100-200 times the weight of keto acid (3) is used.Frequently, a cosolvent such as acetic acid is also employed to increasethe solubility of the reactants. If it is desired to produce a keto acid(4) wherein X is Br or I, the hydrochloric acid is replaced byhydrobromic or hydriodic acid respectively. Keto acid (4) is thenoxidized (4→5) under Bayer-Villiger conditions with peracetic acid,perbenzoic acid, m-chloroperbenzoic acid or m-nitroperbenzoic acid.About one equivalent of this oxidizing agent is used in a reaction inertsolvent such as methylene chloride or chloroform. The reaction iscarried out conveniently at a temperature of from about 25°-40° C. Thereaction proceeds more rapidly at the high temperatures. Slightlyincreased yields may be obtained if the reaction is run in the presenceof one equivalent of sodium carbonate or sodium bicarbonate. Lactoneacid (5) is then reduced to lactone alcohol (6) by a two-step procedurecomprising contacting lactone acid (5) with a lower alkyl halo carbonatein a reaction inert solvent containing an equivalent of an organic basesuch as triethylamine or triethyldiamine. This reaction is bestconducted below room temperature and most conveniently between -20° and±10° C in a reaction inert solvent, typically dimethoxyethane ortetrahydrofuran. The reaction mixture is then contacted with about from1 to 2 equivalents of sodium borohydride or zinc borohydride indimethoxyethane and the reaction temperature is maintained from about-20° to ±20° C. The reaction is temperature held between these limitsuntil reaction is substantially complete. Any reducing agent may be usedwhich does not reduce the lactone ring, however, sodium or zincborohydride have been found to be most effective. Similarly, for thefirst step of the conversion (5→6) any lower alkyl halo carbonate may beused but ethyl or methyl chlorocarbonate have been found to be mosteffective.

Halo lactone alcohol (6) is converted to lactone ether (7) by firstprotecting the alcohol with an acid labile protecting group such astetrahydropyranyl, 4 methoxypyranyl or trimethylene silyl. Thistransformation is typically accomplished by treating lactone alcohol (6)with an excess of dihydropyran in the presence of a trace of acidcatalyst. P-toluenesulfonic acid is typically employed as a catalyst.After the reaction is substantially complete the excess dihydropyran isremoved and the crude ether thus obtained is dissolved in a reactioninert solvent such as tetrahydrofuran or dimethoxyethane and treatedwith an aqueous lithium hydroxide in the presence of hydrogen peroxide.##STR33## The presence of hydrogen peroxide has been found to be ofsubstantial importance and 30% hydrogen peroxide is preferred. Thepreferred ratio of hydrogen peroxide to THP ether is about 20:1. Thereaction is conveniently conducted at room temperature althoughtemperatures between -5°-50° may be employed. After reaction is completethe product is isolated.

The conversion (7→8) is carried out by a simple esterification reactionin which lactone alcohol (7) is dissolved in an organic base, typicallypyridine or other tertiary amine, and parabiphenyl carboxylic acidchloride is added and the reaction stirred at room temperature untilsubstantially complete. The reaction mixture is then hydrolyzed withdiluted hydrochloric acid at room temperature until thetetrahydropyranyl protecting group has been removed. Extraction of thereaction mixture with a suitable solvent such as ethyl acetate affordsthe desired key intermediate (8). This intermediate is converted byroutes well known in the art to prostaglandins of the A, E and F seriesand numerous prostaglandin analogs. However, if it is desired to prepareprostaglandins of the Fβ series another intermediate may be preparedwhich allows the synthesis of these Fβ prostaglandins by a simplifiedroute. This intermediate may be prepared from keto acid (3) in thefollowing way:

Keto acid (3) is contacted with aqueous sulfuric acid at 150° untilreaction is substantially complete. The resulting keto lactone (15) isthen isolated by solvent extraction. Ethyl acetate is most convenientlyemployed for this purpose. A wide range of sulfuric acid concentrationsmay be used, however, 25% aqueous sulfuric acid has been found to bemost effective. Other acids may also be used in place of sulfuric acidsuch as phosphoric or perchloric acids. Temperatures from about100°-175° are optimum and especially preferred is 150°. The reaction isbest run in a sealed vessel to permit achievement of the desiredreaction temperature. The product of this reaction can be purified mostconveniently by sublimation at 150° and .1 mm.

Keto lactone (15) is then oxidized under Bayer-Villiger conditions todilactone (16). For the purposes of this oxidation, peracetic acid,perbenzoic acid, m-chloroperbenzoic acid or m-nitroperbenzoic acid canbe used. M-chloroperbenzoic acid has been found to be most effective.The reaction is run in a reaction inert solvent in the presence ofanhydrous sodium carbonate. The solvent for these reactions is mosttypically methylene chloride although other reaction inert solvents suchas carbon tetrachloride may be used. Approximately one equivalent of theoxidizing agent is preferred and similarly one equivalent of anhydroussodium carbonate has also been found optimum. The reaction may also berun in the absence of sodium carbonate and under these circumstancesreduced yields are sometimes obtained. The reaction temperature ismaintained from about 25°-40° C by external heating. A temperature of35° has been found optimum. The product is isolated by first washing theorganic layer of aqueous sodium bicarbonate followed by aqueoussaturated sodium sulfate solution and subsequently brine. The organicphase is then dried and evaporated to provide dilactone (16).

Dilactone (16) is then reduced to the lactone hemiacetal (17) by use ofdiisobutyl aluminum hydride. Low temperatures, typically -78°, areemployed although any temperature which does not give rise to overreduction of the molecule is satisfactory. The solvent for this reactionis most usually toluene although any reaction inert solvent which isliquid at the reaction temperature may be used. The steps (17→21) arewell known in the art of prostaglandin synthesis. (17→18) is a Wittigreaction in which hemiacetal (17) is reacted with 4 carbohydroxyn-butyltriphenylphosphonium bromide in diemthyl sulfoxide in thepresence of methylsulfinylmethide. (18→19) is accompanied in the samemanner as (16→17) and hemiacetal (19) is reacted with keto phosphonate(23) in the presence of sodium hydride in a reaction inert solventusually dimethoxyethane to produce keto acid (20).

Keto acid (20) is then reduced by methods well known in the art toprostaglandin F₂β (21). Zinc borohydride or lithium triethyl borohydridemay be used for this purpose and the solvent is most usuallydimethoxyethane. Steps (17→21) are similar to those described by E. J.Corey et al., JACS, 92, 2586 (1970); JACS, 93, 1490 (1971); JACS 93,4327 (1971); and Schaaf and Corey, JOC, 37, 2921 (1972). Keto lactone(15) may also be prepared from the known keto ether (9). (9→10) isaccompanied by contacting keto (9) with borotrifluoride etherate inacetic anhydride at a temperature of from about 0°-20°. The resultingacetate (10) is not isolated but hydrolyzed directly with aqueous base,typically sodium or potassium carbonate, to alcohol (11). Alcohol (11)is then ketalized with ethylene glycol to produce ketal (12). Any acidlabile ketone protecting group such as hemithioketal or dilower alkylketal can be used and the conditions for preparing these ketals orhemithioketals are well known in the art. The ethylene glycol ketal isprepared by refluxing a mixture of keto alcohol (11) in a reaction inertsolvent with ethylene glycol and p-toluenesulfonic acid as a catalystwhile azeotropically removing the water formed by the reaction. Benzeneis most commonly used as a solvent for this reaction although toluene orother alkyl substituted benzenes may also be used. Other acidiccatalysts may also be used such as benzene sulfonic acid, however,p-toluenesulfonic acid is most frequently employed.

Ketal alcohol (12) is then cyclized in a mixture of aqueous mercuricacid and tetrahydrofuran followed by reduction with sodium borohydride.The reduction should be carried out in a strong basic medium and toaffect this before the sodium borohydride solution is added the mixtureis made basic with sodium hydroxide solution. The reducing agent may besodium borohydride, potassium borohydride or zinc borohydride, however,sodium borohydride is most commonly employed. The ketal ether (13) isthen oxidized with ruthium tetraoxide in carbon tetrachloride. Thisreaction requires a very large excess of ruthium tetraoxide unlesssodium or potassium periodate is present in the reaction mixture forregenerating the ruthium tetraoxide. If sodium or potassium periodate isemployed the excess may be reduced to approximately 10 times the weightof ether lactone (13). Lower ratios of ruthium tetraoxide lead toreduced yields and/or longer reaction times. The ketal lactone (14) maythen be hydrolyzed with aqueous dilute mineral acid to produce ketolactone (15).

This reaction may be facilitated by the addition of inert solvents suchas tetrahydrofuran to increase solubility of the reactants. The reactiontemperature is not critical and temperatures of from about 25°-50° aremost commonly employed.

Compound 6 can also be prepared by a still shorter route from compound 2or diester 23 wherein R is hydrogen or lower alkyl is hydrolyzed bycontacting diester 23 with aqueous mineral base such as alkylene metalcarbonate or hydroxide at temperatures from about 0°-100° to producediol 24. Diol 24 is then converted to mono ester 25 by contacting itwith one equivalent of lower alkanoic acid anhydride and a protonacceptor in a reaction inert solvent at a temperature of from about0°-50° until reaction is substantially complete. The proton acceptor canbe organic base such as triethylenediamine or triethylamine and thereaction inert solvent conveniently benzene or if desired, the reactionmay be run in pyridine which will serve as a base and a solvent. In sucha situation, no additional base is necessary. Mono ester 25 is thenoxidized to keto ester 26 by contacting it with about two equivalents ofchromium trioxide in reaction inert solvent at a temperature of fromabout 0°- 25° until reaction is substantially complete. Jones'conditions, that is to say, chromium trioxide, sulfuric acid, acetoneare preferred, however, other oxidative means such as chromium trioxidepyridine are also satisfactory. Keto ester 26 is then converted to haloketone 27 by refluxing with concentrated with 10 to 100 times its weightof concentrated hydrochloric acid at a temperature of from about100°-150° until reaction is substantially complete. The bromo ketone canbe obtained in a similar way by substituting hydrobromic acid forhydrochloric acid in the above reaction. Compound 27 is then convertedto compound 6 by means of Bayer-Villiger oxidation in the mannerdescribed for the conversion of (4→5) in the synthesis described above.The order of the last two steps may be inverted by first oxidizing ketoester 26 to a lactone ester which is then refluxed with the desired haloacid to provide compound 6.

A special advantage of the synthetic sequences of this invention is thatfor the intermediate products are easy to isolate and purify. In most ofthe sequences no chromatography is required. Furthermore, the novelsynthetic sequences of the present invention require very simple andinexpensive starting materials and are readily adaptable to large scalepreparations.

In the synthesis described above where ketals are used as ketoneprotecting groups the obvious equivalents of ethylene glycol ketals suchas hemithioketals or a dilower alkyl ketals will be clear to thoseskilled in the art. Likewise, in other reaction steps described hereinsuch as oxidation of alcohols to ketals the reaction conditions are notcritical and a wide variety of known techniques will occur to thoseskilled in the art.

The invention claimed is not limited to the specific conditions cited inthe examples to follow. Melting points and boiling points are given indegree of Centigrade. All melting and boiling points are corrected.Infrared data is given in microns, MNR is given in parts per millionusing TMS as a standard. The following examples are merely illustrativeand in no way limit the scope of the appended claims.

EXAMPLE I 3-Hydroxymethyl tricyclo [2.2.1.0²,6 ]heptan-5-ol bisformate(1')

To a stirred solution of 39.9 g paraformaldehyde in formic acid (800 ml)and conc. H₂ SO₄ (15 ml) under nitrogen and at 20° C was added dropwise132 g norbornadiene while keeping the temperature between 20°-25° C.After 1.5 hr. the reaction was quenched by adding to 800 ml ofice-water. Extraction with ether (3 × 750 ml), washing the organic layerwith water (1 × 250 ml), brine (3 × 250 ml) and drying (Na₂ SO₄)afforded the crude 3-hydroymethyl tricyclo [2.2.1.0²,6 ]heptan-5-olbisformate (1') as an oil. Distillation, after a forerum of bp.40°C/15mm, gave 235g pure tricyclenebisformate, bp. 104° C/0.3 mm (84%yield).

IR, 5.81 and 8.55 μ (CHCl₃)

NMR, 8.1 (singlet, 2H), 4.8 (1H), 4.1 (triplet, 2H) δ.

3-carboxy tricyclo [2.2.1.0²,6 ]heptan-5-one (2')

To a cooled solution of 58.8 g tricyclene bisformate (1') in acetone(1,200 ml) at 0° C with vigorous stirring was added 2.67 M Jones reagent(370 ml) over a period of 10 min, maintaining the temperature below 5°C. After stirring overnight, the reaction was quenched by addition ofisopropanol (20 ml) followed by addition of solid NaCl (500 g). Thereaction mixture was filtered, solids washed with ethylacetate, and thecombined filtrate after evaporation afforded the crude 3-carboxytricyclo [2.2.1.0²,6 ]heptan-5-one (2'). Crystallization from ethylacetate gave colorless crystals, m.p. 144°-145° C, of pure tricycleneketoacid (34 g, 72% yield).

IR, 5.68 and 5.85 μ (CHCL₃)

NMR, 9.5 (1H, exchangeable), 3.1 (singlet, 1H), 2.35 (multiplet, 3H),2.0 (singlet, 2H), 1.55 triplet, 1H) δ.

Optically active material had m.p. 138°, [α ]_(D) ²⁵ + 74° (C 1.0 MeOH)

EXAMPLE III Lactone of 5-hydroxy-2-oxo-bicyclo[2.2.1]heptan-7-oic acid(3')

A solution of the ketoacid (2') (182 mg) in 25% aq. H₂ SO₄ was refluxed(bath temperature, 150° C) for 12 hr. The cooled mixture was treatedwith solid sodium chloride, and extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried (Na₂ SO₄)and concentrated. Sublimation of the crude product at 150° C/0.1 mmafforded 132 mg (70% yield) of lactone of5-hydroxy-2-oxo-bicyclo[2.2.1]heptan-7-oic acid (3'), m.p. 195°-96° C.

IR, 5.59, 5.69, 10.20 and 10.52 μ (CHCl₃)

NMR, 4.9 (1H), 3.3 (1H), 3.15-2.6 (2H), 2.3 (2H), 2.2-1.9 (2H) δ

Optically active material had m.p. 196°-97√ C, [α ]_(D) ²⁵ + 270°.

EXAMPLE IV

(2β-carboxyl-3α,5β-dihydroxy-cyclopent-1α-(yl)acetic acid, γ, δ-lactone)(4').

To a stirred mixture of 196 mg ketolactone (3'), 328 mg anhydrous Na₂CO₃ in methylene chloride (10 ml) was added 276 mg m-chloroperbenzoicacid over a period of 1.5 hr. and temperature maintained at 35° C byexternal heating. After 4 hr. the reaction mixture was cooled, filteredand the organic layer washed with saturated NaHCO₃ (1 × 5 ml), saturatedNa₂ SO4 (1 × 5 ml), brine (1 × 5 ml), dried (Na₂ SO₄) and evaporated togive 150 mg of pure (2β-carboxyl-3α,5β-dihydroxy-cyclopent-1α-yl)aceticacid, γ, δ-lactone (4').

IR, 5.57 and 5.71 μ (CHCl₃)

Mass spectrum, M+at 168.

EXAMPLE V 5-Chloro-2-oxo-bicyclo[2.2.1]heptan-7-oic acid (5')

A continuous stream of HCl gas was passed into a refluxing solution of5.0 g of the ketoacid (2') in water (250 ml) for 4 hr. The reactionmixture was evaporated to dryness under reduced pressure and the residuecrystallized from ether to give pure5-chloro-2-oxo-bicyclo[2.2.1]heptan-7-oic acid (5').

Optically active material had m.p. 156°, [α ]_(d) ²⁵ + 14° (C. 1.0 MeOH)

EXAMPLE VI (2β-Carboxy-3α-hydroxy-5β-chlorocyclopent-1α-yl)acetic acid,β-lactone (6')

A mixture of 188 mg chloro ketoacid (5'), 0.265 g 40% peracetic acid,117 mg NaHCO₃ in methylene chloride (10 ml) was stirred and heated at35° C for 5 hr. The reaction mixture was cooled, filtered and evaporatedto dryness. Crystallization of the residue from ether afforded 140 mg(70% yield) of (2β-carboxy-3α-hydroxy-5β-chlorocyclopent-1α-yl) aceticacid, δ-lactone (6'), m.p. 180°-81° C.

Optically active material had mp 166°, [α ]_(D) ²⁵ -70° (C. 1.0 MeOH).

EXAMPLE VII2[2β-tetrahydropyran-2-yloxymethyl-3α-hydroxy)-5α-hydroxycyclopent-1α-yl]aceticacid, γ-lactone (8')

To a solution of chloro alcohol (7') (229 mg) in methylene chloride (10ml) was added dihydropyran (0.32 ml) and a catalytic amount ofp-toluenesulfonic acid. After 1 hr. the reaction mixture was washed withbrine, dried (Na₂ SO₄) and evaporated to a colorless oil. The crudeTHP-ether thus obtained was dissolved in THF (6.5 ml) and heated with30% H₂ O₂ (3.3 ml) followed by a solution of LiOH (29 mg) in water (3.3ml). The solution was stirred 1 hr. at room temperature, diluted withethyl acetate (35 ml) and washed with saturated Na₂ SO₃ (10 ml). Afterdrying (Na₂ SO₄) evaporation afforded 260 mg of the desired2[2β-tetrahydropyran-2-yloxymethyl-3α-hydroxyl)-5α-hydroxycyclopent-1α-yl]aceticacid, γ-lactone (8'). IR, 1770 cm⁻¹ (CHCl₃).

EXAMPLE VIII 2 [ 2β-hydroxymethyl-3α-p-phenylbenzoyloxy-5α-hydroxycyclopentan1α-yl]acetic acid, γ-lactone.

To a solution of the γ-lactone (8') (44 mg) in pyridine (0.27 ml) wasadded p-biphenylcarboxylic acid chloride (46 mg) and the mixture stirredovernight. The reaction was quenched by adding a little methanol, andstirred with dilute HCl (2 ml) for 6 hrs to remove the THP group.Extraction with ethyl acetate afforded 32 mg of the desired2[2β-hydroxymethyl-3α-p-phenylbenzoyloxy-5α-hydroxycyclopentan-1α-yl]acetic acid, γ-lactone, mp 130°-31°, [ α]_(D) ²⁵ =-86.5° (C 1.0 CHCl₃).

EXAMPLE IX (2 β-Hydroxymethyl-3α-hydroxy-5 β-chlorocyclopent-1 α-yl)acetic acid, δ-lactone (7')

To a solution of chloro acid lactone (6') (1.43 g, 7 mmole) in 28 mltetrahydrofuran cooled to 0° and under nitrogen, was added 0.756 g (7mmole) of ethyl chloro formate followed by dropwise addition of asolution of 0.70 g (7 mmole) triethylamine in 14 ml tetrahydrofuran. Aprecipitate formed immediately and the cold mixture stirred for 10 min.The reaction mixture was filtered under a nitrogen cover and thefiltrate kept at 0°. The filtered solid was washed with coldtetahydrofuran (2 × 5 ml). The combined filtrate was stirred at 0° and5.2 ml. (5.2 mmole) of a 1M solution of zinc borohydride in DME wasadded dropwise. The reaction mixture was quenched with saturated sodiumbitartrate, diluted with 50 ml methylene chloride and dried over sodiumsulfate. Filtration and evaporation gave the crude chloro lactonealcohol (1.46 g yield 100%) which was purified by column chromatography,to give 1.2 g of pure (2β-hydroxymethyl-3α-hydroxy-5β-chlorocylcopent-1αyl)acetic acid, δ-lactone (7).

IR: 1735 cm⁻¹

NMR 4.95 (1H, M), 4.30 (1H, double doublet), 3,90 (2H, doublet), 7.0cps) δ

Optically active material

mp 130°, [α ]_(D) ²⁵ -65°(C ). CHCl₃) EXAMPLE X 7-hydroxymethyl bicyclo[2.2.1]hept-2-ene-6-one acetate 10').

A cooled (0° C), stirred solution of 4.99 g 7-hydroxymethyl bicyclo[2.2.1.]hept-2-ene-6-one benzyl ether in acetic anhydride (109 ml) wastreated with BF₃ -etherate (0.63 ml). After 15 min., the reaction wasquenched by addition of water (19 ml) and the mixture evaporated invacuo to dryness, affording 3.9 g oily 7-hydroxymethyl bicyclo[2.2.1]hept-2-ene-6-one acetate (10').

IR, 5.73 μ (CHCl₃).

NMR, 6.50 (9, 1H), 6.0 (1H), 4.15 (d, J=7 cps, 2H), 2.05 (S, 3H)δ.

EXAMPLE XI 7-hydroxymethylbicyclo[2.2.1.]hept-2-ene-6-one (11')

Powdered, dry K₂ CO₃ (1.51 g) was added to stirred solution of theketoacetate (10') (1.96 g) in methanol (45 ml) at room temperature.After 20 min, 6N HCl (3.6 ml) was added and the mixture evaporated todryness. The residue was extracted with ethyl acetate to give 1.0 g of7-hydroxymethyl bicyclo[2.2.1]hept-2-ene-6-one (11') homogenous on tlc(Rf 0.25, C₆ H₆ :MeOH, 17:3).

IR, 5.74 μ (CHCl₃).

EXAMPLE XII 7-hydroxymethyl bicyclo[2.2.1]hept-2-ene-6-one ketal (12')

A mixture of ketoalcohol (11') (1.05 g), ethylene glycol (0.98 g) andp-toluene sulfonic acid (0.16 g) in benzene (250 ml) was refluxed 16hr., while water was removed azeotropically. The cooled solution waswashed with saturated NaHCO₃ (1 × 10 ml), brine (1 × 10 ml), dried (Na₂SO₄) and evaporated to the oily 7-hydroxymethylbicyclo[2.2.1]hept-2-ene-6-one (12') ketal, 1.1 g.

IR, 2.75-3.15 (OH) μ (neat)

NMR, 5.80-6.30 (2H), 3.95 (singlet, 4H), 3.55 (d, J=7.0, 2H), 2.0 (dd,J=13.5 & 3.5, 1H), 1.55 (d, J=13.5. 1H) δ.

EXAMPLE XIII 6-oxo-9-oxatricyclo[4.3.0.0³,7 ]nonane ketal (13')

To a stirred yellow mixture of 4.0 g Hg (OAc)₂ in H₂ O-THF (1:1) (12.6ml) was added 1.15 g ketal alcohol (12') dissolved in THF (1.5 ml). Theyellow color disappeared within 5 min., and 3 M NaOH (6.3 ml) was addedto the reaction mixture followed by 6.3 ml of 0.5 ml NaBH₄ solution in 3M NaOH. The precipitated mercury was filtered off, solid NaCl added tothe filtrate and extracted with ethyl acetate. Concentration of organicextracts afforded 720 mg of oily 6-oxo-9-oxatricyclo [4.300³,7 ]nonaneketal (13') homogenous on tlc (Rf 0.52, CH Cl :MeOH, 19:1).

NMR, 4.2 (1H). 4.1-3.6 (6H), 2.8-1.2 (7H) δ.

EXAMPLE XIV 2-hydroxy-5-oxo-bicyclo[2.2.1]heptan-7-oic acid ketal (14)

A mixture of 0.58 g ether ketal (13) in 3% RuO₄ solution in CCl₄ (2 ml)and 10 ml of saturated aqueous NaIO₄ was stirred 18 hr. at roomtemperature. The black precipitate was filtered off, and the organiclayer separated, dried (Na₂ SO₄), gave 47 mg of2-hydroxy-5-oxo-bicyclo[2.2.1]heptan-7-oic acid (14) ketal as an oil,homogenous on tlc (Rf 0.45, C₆ H₆ :EtOAC, 3:1).

IR, 5.63 μ (CHCl₃)

Treatment with acid afforded the ketolactone (3).

EXAMPLE XV 3-Hydroxymethyltricyclo [2.2.1.0²,6 ]heptan-5-ol (15')

To a stirred refluxing solution of 5 g of tricyclene bisformate (1') inmethanol (20 ml) is added 0.5 g of sodium methoxide and the resultingmethylformate distilled off. After completion of reaction CO₂ is bubbledinto the reaction mixture, solids are filtered off and solventevaporated to dryness to give 3-hydroxymethyltricyclo [2.2.1.0²,6]heptan-5-ol (15').

EXAMPLE XVI 3-Acetoxymethyltricyclo [2.2.1.O²,6 ]heptan-5-ol (16')

To a stirred solution of 14 gm of the diol (15') in 100 ml pyridine isadded acetic acid. The reaction is stirred overnight at 25° and quenchedby addition of ice-water. The product is extracted with CH₂ Cl₂. The CH₂Cl₂ layer washed with dil. HCl, dried (Na₂ SO₄) and concentrated to give3-acetoxymethyltricyclo [2.2.1.0²,6 ]heptan-5-ol (16').

EXAMPLE XVII 3-Acetoxymethyltricyclo [2.2.1.0²,6 ] heptan-5-one (17')

To a cooled solution of 6 gm acetoxy alcohol (16' ) in 150 ml acetone at0° C with vigorous stirring in added 2.67 M Jones reagent (40 ml) over aperiod of 10 min. After stirring 5 hr., the reaction is quenched byaddition of isopropanol (2 ml) followed by dilution with water.Extraction with CH₂ Cl₂ affords the title product.

EXAMPLE XVIII 2-Acetoxymethyl-3-hydroxy-bicyclo [3.1.0]hexan-6-oic acidlactone (18')

To a stirred mixture of 2 acetoxy ketone (17') in methylene chloride(100 ml) is added 2.8 g m-chloroperbenzoic acid and the solutionrefluxed for 6 hr. The reaction mixture is cooled, filtered and theorganic layer washed with saturated NaHCO₃, saturated Na₂ SO₄, brine,dried (Na₂ SO₄) and evaporated to give 2-acetoxymethyl-3-hydroxy-bicyclo[3.1.0]hexan-6-oic acid lactone (18').

EXAMPLE XIX 2β-Hydroxymethyl-3α-hydroxy-4β-chloro-cyclopent-1α-yl)aceticacid δ-lactone (7')

A mixture of 2 g acetoxy lactone (18') and concentrated HCl (20 ml) isrefluxed for 4 hr. The reaction mixture is evaporated to dryness underreduced pressure and the residue crystallized from ether to give pure2β-hydroxymethyl-3α-hydroxy-4β-chlorocyclopent-1α-yl)acetic acid,δ-lactone (7').

What is claimed is:
 1. A process for the preparation of a lactone of thestructure: ##STR34## wherein THP is tetrahydropyranyl which comprisescontacting a halo lactone of the formula ##STR35## wherein X is halogenwith an equimolar amount of dihydropyran in presence of a catalyticamount of a strong acid and contacting the resulting ether with anequimolar amount of alkali metal hydroxide and twenty times its weightof 30% hydrogen peroxide in aqueous tetrahydrofuran at a temperature offrom about -10° to 30° C until reaction is substantially complete andisolation of product.
 2. A process of claim 1 wherein the starting halolactone alcohol is prepared by a process comprising contacting a haloketone of structure: ##STR36## with one equivalent of peracetic acid ina reaction inert solvent at a temperature of from about 20°-40° C untilreaction is substantially complete and isolating the product so formed.3. A process of claim 2 wherein the starting halo ketone is prepared bya process comprising contacting a ketone of structure: ##STR37## whereinR is lower alkyl; with 10-100 times its weight of concentratedhydrochloric acid at a temperature of from about 100°-150° untilreaction is substantially complete and isolating the product so formed.4. A process of claim 3 wherein the starting tricyclene ketone isprepared by a process comprising contacting a tricyclene alcohol ofstructure: ##STR38## wherein R is lower alkyl; with about twoequivalents of CrO₃ in a reaction inert solvent at a temperature of fromabout 0-25° until reaction is substantially complete and isolating theproduct so formed.
 5. A process of claim 4 wherein the startingtricyclene alcohol is prepared by a process comprising contacting a diolof structure: ##STR39## with one equivalent of lower alkanoic acidanhydride and a proton acceptor in a reaction inert solvent at atemperature of from about 0°-50° C until reaction is substantiallycomplete and isolating the product so formed.
 6. A process of claim 5wherein the starting diol is prepared by a process comprising contactinga compound of the structure: ##STR40## wherein R is hydrogen or loweralkyl; with an aqueous solution of an alkali metal hydroxide orcarbonate at a temperature of from about 0°-50° C until reaction issubstantially complete.